4-oxo-1,2,3-benzotriazines

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein X is N or CH; 
     R 1  and R 2  are the same or different and are hydrogen, halogen, CF 3 , C 1-6  alkyl, C 1-7  acyl, C 1-7  acylamino, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C 1-6  alkyl or C 3-8  cycloalkyl groups, or by C 4-5  polymethylene or by phenyl, C 1-6  alkylsulphonyl, C 1-6  alkylsuphinyl, C 1-6  alkoxy, C 1-6  alkylthio, hydroxy or nitro; or R 1  and R 2  taken together are methylenedioxy or ethylenedioxy; 
     Z is a group of formula (a), (b) or (c) ##STR2## wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and 
     R 3  or R 4  is C 1-4  alkyl; 
     having 5-HT 3  receptor antagonist activity, a process for their preparation and their use as pharmaceuticals.

This invention relates to novel compounds having useful pharmacologicalproperties, to pharmaceutical compositions containing them, to a processand intermediates for their preparation, and to their use aspharmaceuticals.

EP-A-220011 (Beecham Group p.l.c.) describes a class of benzamideshaving an azabicyclic side chain, and possessing 5-HT₃ receptorantagonist activity, and gastric motility enhancing activity.

A class of novel, structurally distinct compounds has now beendiscovered. These compounds have 5-HT₃ receptor antagonist activity andgastric motility enhancing activity.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt thereof: ##STR3## wherein X is Nor CH;

R₁ and R₂ are the same or different and are hydrogen, halogen, CF₃, C₁₋₆alkyl, C₁₋₇ acyl, C₁₋₇ acylamino, or amino, aminocarbonyl oraminosulphonyl, optionally substituted by one or two C₁₋₆ alkyl or C₃₋₈cycloalkyl groups, or by C₄₋₅ polymethylene or by phenyl, C₁₋₆alkylsulphonyl, C₁₋₆ alkylsuphinyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxyor nitro; or R₁ and R₂ taken together are methylenedioxy orethylenedioxy;

Z is a group of formula (a), (b) or (c) ##STR4## wherein n is 2 or 3; pis 1 or 2; q is 1 to 3; r is 1 to 3; and R₃ or R₄ is C₁₋₄ alkyl.

Preferably X is N.

Suitable examples of the groups R₁ and R₂ include the following groups;hydrogen, chlorine, bromine, methyl, ethyl, amino, methylamino,dimethylamino, C₁₋₄ alkanoylamino such as formylamino, acetylamino,propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino andaminosulphonyl substituted by one or two methyl, ethyl, n- oriso-propyl, n-, sec-, iso- or tert-butyl or phenyl groups, nitro,methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- andiso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl.

Particularly suitable R₁ and R₂ groups include hydrogen, halogen,methoxy, optionally substituted amino and aminosulphonyl as defined andC₁₋₆ alkylsulphonyl.

It is generally preferred that R₁ is in the 6-position and R₂ is in the7-position.

Preferred R₂ groups include hydrogen, 7-halo, such as 7-bromo and7-chloro, and 7-amino. R₁ groups of interest include optionallysubstituted 6-aminosulphonyl as defined and 6-C₁₋₆ alkylsulphonyl or-sulphinyl, such as 6-aminosulphonyl and 6-methylsulphonyl, hydrogen,and 6-halo as for R₂ 7-halo.

When R₁ and R₂ taken together are methylenedioxy or ethylenedioxy, R₁and R₂ are preferably ethylenedioxy.

Often the 3-nitrogen and the side chain nitrogen atom are separated by2, 3 or 4 carbon atoms, preferably 2 or 3. Examples of R₃ /R₄ aremethyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl,preferably methyl.

Preferably n is 2 and p, q and r are 1 or 2.

The pharmaceutically acceptable salts of the compounds of the formula(I) include acid addition salts with conventional acids such ashydrochloric, hydrobromic, boric, phosphoric, sulphuric acids andpharmaceutically acceptable organic acids such as acetic, tartaric,lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic,α-keto glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

The pharmaceutically acceptable salts of the compounds of the formula(I) are usually acid addition salts with acids such as hydrochloric,hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and aceticacid.

Preferably the acid addition salt is the hydrochloride salt.

Examples of pharmaceutically acceptable salts include quaternaryderivatives of the compounds of formula (I) such as the compoundsquaternised by compounds R_(a) -T wherein R_(a) is C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and T is a radical correspondingto an anion of an acid. Suitable examples of R_(a) include methyl, ethyland n- and iso-propyl; and benzyl and phenethyl. Suitable examples of Tinclude halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts of compounds of formula(I) also include internal salts such as pharmaceutically acceptableN-oxides. The compounds of the formula (I), their pharmaceuticallyacceptable salts, (including quaternary derivatives and N-oxides) mayalso form pharmaceutically acceptable solvates, such as hydrates, whichare included wherever a compound of formula (I) or a salt thereof isherein referred to.

It will of course be realised that some of the compounds of the formula(I) have chiral or prochiral centres and thus are capable of existing ina number of stereoisomeric forms including enantiomers. The inventionextends to each of these stereoisomeric forms (including enantiomers),and to mixtures thereof (including racemates). The differentstereoisomeric forms may be separated one from the other by the usualmethods.

It will also be realised that the benzodi/tri-azinone nucleus incompounds of formula (I) may adopt an endo or exo configuration withrespect to Z. The endo configuration is preferred.

A group of compounds within formula (I) is of formula (II): ##STR5##wherein the variables are as defined in formula (I).

Examples of the variables and preferred variables are as so describedfor corresponding variables in relation to formula (I).

A further group of compounds within formula (I) is of formula (III):##STR6## wherein q¹ is 1 or 2 and the remaining variables are as definedin formulae (I) and (II).

Examples of the variables and preferred variables are as so describedfor the corresponding variables in formula (I).

There is a further group of compounds within formula (I) of formula(IV): ##STR7## wherein r¹ is 1 or 2 and the remaining variables are asdefined in formulae (I) and (II).

Examples of the variables and preferred variables are so described asthe corresponding variables in formula (I).

The invention also provides a process for the preparation of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, whichprocess comprises cyclising a compound of formula (V): ##STR8## wherein(when X is N), Y is a group --N₂ ⁺ L⁻ wherein L⁻ is an anion of an acid;or (when X is CH), Y is a group --NHCHQ₁ Q₂ where Q₁ and Q₂ are bothleaving groups, or Q₁ and Q₂ together form an oxo group; Z¹ is Z asdefined or Z wherein R₃ /R₄ is replaced by a hydrogenolysable protectinggroup; and the remaining variables are as hereinbefore defined; andthereafter converting Z¹, when other than Z, to Z; optionally convertingR₃ and/or R₄ to other R₃ and/or R₄ ; and optionally forming apharmaceutically acceptable salt of the resultant compound of formula(I).

The counter-ion L⁻ is generally a strong inorganic acid anion such aschloride, bromide, hydrogen sulphate, or a complex polyhalo anion, suchas tetrafluoroborate or hexafluorophosphate.

Suitable values for Q₁ and Q₂ include C₁₋₄ alkoxy, such as ethoxy or Q₁and Q₂ together form an oxo group.

When Y is --N₂ ⁺ L⁻ as defined, the compound of the formula (XXII) isoften present in aqueous acidic solution having been prepared in situ byconventional diazotisation. Basification for example with an alkalimetal hydroxide such as sodium hydroxide or an alkali metal weak acidsalt such as sodium acetate generally effects cyclisation.

When Q₁ and Q₂ are such a group readily displaceable by a nucleophile,for example C₁₋₄ alkoxy, or together are oxo, cyclisation is generallyeffected in an inert solvent by heating under acid or base catalysis toa non-extreme elevated temperature, for example under solvent reflux.The compound of formula (V) is often generated in situ especially whenQ₁ and Q₂ together are oxo, and in these cases the solvent will be thatused in the preparation, or an excess of one of the preparativereagents.

The (in situ) preparation of compounds of the formula (V) is describedhereinafter.

It will be apparent that compounds of the formula (I) containing an R₁or R₂ group which is convertible to another R₁ or R₂ group are usefulnovel intermediates.

The skilled person will appreciate that the choice or necessity ofconversion of groups R₁ and/or R₂ to other groups R₁ and/or R₂ will bedictated by the nature and position of substituents R₁ and/or R₂.

It will be apparent that compounds of the formula (I) containing an R₁or R₂ group which is convertible to another R₁ or R₂ group are usefulintermediates, and as such form an important aspect of the invention. Byway of example of such conversions, the compounds of the formula (I)wherein R₁ or R₂ is a nitro group may be prepared via the nitration ofthe corresponding intermediate product wherein R₁ or R₂ is a hydrogenatom.

Also the reduction of the intermediates wherein R₁ or R₂ is a nitrogroup to R₁ /R₂ amino may be effected with reagents known to be suitablefor reducing nitroarenes to aminoarenes.

Those compounds of the invention wherein R₁ or R₂ is a C₁₋₇ acylaminogroup may be prepared from the corresponding intermediate wherein R₁ orR₂ is an amino group by reaction with a conventional acylatingderivative. For an R₁ /R₂ fromamido group acylation may be effected withthe free acid.

This invention thus also provides an optional process (I) wherein R₁ orR₂ is an amino group which process comprises the deacylation of acorresponding intermediate wherein R₁ or R₂ is a C₁₋₇ acylamino group.

Generally the hydrolysis reaction may be effected by treatment with abase such as an alkali metal hydroxide.

Also a compound of the formula (I) wherein R₁ or R₂ is halogen may beprepared by a conventional halogenation of the correspondingintermediate wherein the said R₁ or R₂ is hydrogen.

Similarly the compounds wherein R₁ or R₂ is C₁₋₆ alkylthio or C₁₋₆alkylsulphinyl may be oxidised to the corresponding compounds wherein R₁or R₂ is C₁₋₆ alkylsulphinyl or C₁₋₆ alkylsulphonyl respectively. Theseoxidations may conveniently be carried out conventionally at belowambient temperatures using an organic peracid in a non-aqueous inertreaction medium, preferably a chlorinated hydrocarbon solvent, forexample using 3-chloroperbenzoic acid, or using a water solubleinorganic strong oxidant, such as an alkali metal permanganate orhydrogen peroxide in aqueous solution.

It will be appreciated that, depending on the other specificsubstituents in the compound of the formula (I), such an oxidation on acompound of the formula (I) may also form the N-oxide of the bicyclicmoiety therein.

Given the specific substitution desired and it having been decidedwhether the compound or its N-oxide is required, the skilled man willreadily ascertain whether such R₁ /R₂ interconversion is desirable. Ingeneral it is preferred to effect the oxidation in the intermediate offormula (VIII) as hereinafter defined.

Z¹ when other than Z may have a hydrogenolysable protecting group whichis benzyl optionally substituted by one or two groups independentlyselected from halogen, C₁₋₄ alkoxy, C₁₋₄ alkyl or nitro. Such benzylgroups may, for example, be removed, when R₁ /R₂ is not halogen, byconventional transition metal catalysed hydrogenolysis to give compoundsof the formula (VI): ##STR9## wherein Z² is of formula (d) or (e)##STR10## wherein the variables are as defined in formula (I).

This invention also provides a further process for the preparation of acompound of the formula (I) which comprises N-alkylating a compound offormula (VI), and optionally forming a pharmaceutically acceptable salt,of the resulting compound of the formula (I).

This may be achieved by reaction of the compound of formula (VI) with acompound R₃ Q₃ or R₄ Q₃ wherein R₃ and R₄ are as hereinbefore definedand Q₃ is a leaving group.

Suitable values for Q₃ include groups displaced by nucleophiles such asCl, Br, I, OSO₂ CH₃, OSO₂ C₆ H₄ pCH₃ or OSO₃ CH₃.

Favoured values for Q₃ include Cl, Br and I.

The reaction may be carried out under conventional alkylation conditionsfor example in an inert solvent such as dimethylformamide in thepresence of an acid acceptor such as potassium carbonate. Generally thereaction is carried out at non-extreme temperature such as at ambient orslightly above.

Alternatively, `N-alkylation` may be effected under conventionalreductive alkylation conditions when the group R₃ or R₄ in the compoundof formula (I) contains a methylene group adjacent to the N-atom in thebicycle.

Interconverting R₃ or R₄ in the compound of the formula (VI) beforecyclisation of the compound of formula (V) or on the compound of formula(IX) before coupling with the compound of formula (VIII) as describedhereinafter, is also possible. Such interconversions are effectedconveniently under the above conditions. It is desirable to protect anyamine function with a group readily removable by acidolysis such as aC₂₋₇ alkanoyl group, before R₃ /R₄ interconversion.

The preparation of intermediates for the above preparative processeswill now be described.

Where Y is N₂ ⁺ L⁻ as defined, the compound of the formula (V) isusually generated in situ in solution by the diazotisation of thecorresponding amine of formula (VII): ##STR11## Diazotisation may becarried out conventionally, for example, by the interaction of an alkalimetal nitrite, a strong inorganic acid and the compound of the formula(VII) in aqueous solution at 10° to -10° C.

When Y is NHCHQ₁ Q₂ where Q₁ and Q₂ are each C₁₋₄ alkoxy, for exampleethoxy, the intermediate of formula (V) may be prepared in situ by knownmethods, such as by reacting the compound of the formula (VII) with atri-(C₁₋₄ alkyl) orthoformate.

When Q₁ and Q₂ together are an oxo group, the reaction is preferablycarried out by heating a mixture of the compound of formula (VII) withformic acid at e.g. reflux, using excess of acid as solvent.

Compounds of the formula (VII), in this case, are prepared in situ byreacting compounds of the formula (VIII): ##STR12## with a compound ofthe formula (IX): ##STR13## heating to a non-extreme temperature in aninert solvent.

An alternative method for the preparation of a compound of formula (VII)is by the reduction of a compound of the formula (X): ##STR14## Thereduction may be effected using conventional methods for reducing nitrogroups on aromatic nuclei, for example using Raney nickel, or by theammonolysis of a corresponding compound of the formula (X) wherein the2-nitro group is replaced by halo, such as fluoro or chloro, preferablyfluoro. The ammonolysis may be effected conventionally.

The compounds of the formulae (VII) and (X) may be prepared by thereaction of a compound of the formula (XI): ##STR15## wherein J is NH₂or NO₂ ; Q₃ is a leaving group and the remaining variables are asdefined in formula (I); with a compound of (IX) as hereinbefore defined.

Examples of leaving groups Q₃, displaceable by a nucleophile, includehalogen such as chloro and bromo; C₁₋₄ alkoxy, such as CH₃ O and C₂ H₅O-; PhO-; activated hydrocarbyloxy, such as Cl₅ C₆ O- or Cl₃ CO-;succinimidyloxy; and imidazolyl. Preferably Q₁ is halogen, mostpreferably chloro.

If a group Q₃ is a halide or imidazolyl, then the reaction is preferablycarried out at non-extreme temperatures in an inert non-hydroxylicsolvent, such as benzene, dichloromethane, toluene, diethyl ether,tetrahydrofuran (THF) or dimethylformamide (DMF). It is also preferablycarried out in the presence of an acid acceptor, such as an organicbase, in particular a tertiary amine, such as triethylamine,trimethylamine, pyridine or picoline, some of which can also function asthe solvent. Alternatively, the acid acceptor can be inorganic, such ascalcium carbonate, sodium carbonate or potassium carbonate. Temperaturesof 0°-100° C., in particular 10°-80° C. are suitable.

If a group Q₃ is C₁₋₄ alkoxy, phenoxy, activated hydrocarbyloxy orsuccinimidyloxy then the reaction is preferably carried out in an inertsolvent, such as toluene or dimethylformamide. In this instance, it ispreferred that the group Q₁ is Cl₃ CO- or succinimidyloxy and that thereaction is carried out in toluene at reflux temperature.

The compounds of formula (VIII) and (IX) are known or are preparableanalogously to, or routinely from, known compounds.

Compounds of the formulae (V), (VII) and (X) are novel and form anaspect of the invention.

It will be realised that in the compound of the formula (I) thebenzodi/tri-azinone nucleus may adopt an endo or exo (axial orequatorial) orientation with respect to the ring of the bicyclic moietyto which it is attached. A mixture of endo and exo isomers of thecompound of the formula (I) may be synthesised non-stereospecificallyand the desired isomer separated conventionally therefrom e.g. bychromatography; or alternatively the endo and exo isomer may if desiredbe synthesised from the corresponding endo or exo form of the compoundof the formula (IX).

Pharmaceutically acceptable salts of the compounds of this invention maybe formed conventionally. The acid addition salts may be formed forexample by reaction of the base compound of formula (I) with apharmaceutically acceptable organic or inorganic acid.

The compounds of the present invention are 5-HT₃ receptor antagonistsand it is thus believed may generally be used in the treatment orprophylaxis of emesis, migraine, cluster headaches, trigeminalneuralgia, visceral pain and anxiety. Compounds which are 5-HT₃ receptorantagonists may also be of potential use in the treatment of other CNSdisorders such as psychosis; drug withdrawal syndrome, arrhythmia,obesity and gastrointestinal disorders such as irritable bowel syndrome.

Anti-emetic activity, in particular, includes that of preventingcytotoxic agent or radiation induced nausea and vomiting. Examples ofcytotoxic agents include cisplatin, doxorubicin and cyclophosphamide.

The compounds of the present invention also have gastric motilityenhancing activity, useful in the treatment of disorders such asretarded gastric emptying, dyspepsia, flatulence, oesophagal reflux andpeptic ulcer.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art, for example with an entericcoating.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpolypyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate.

Suitable pharmaceutically acceptable wetting agents include sodiumlauryl sulphate. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups, orelixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, for examplesorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs or are presentedas a dry product for reconstitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, emulsifying agents, non-aqueous vehicles(which may include edible oils), preservatives, and flavouring orcolouring agents.

The oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the compound in a vehicle and filter sterilisingbefore filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure of ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

The invention further provides a method of treatment or prophylaxis ofemesis, migraine, cluster headache, trigeminal neuralgia, visceral painand/or anxiety in mammals, such as humans, which comprises theadministration of an effective amount of a compound of the formula (I)or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders herein-before describeddepends on the relative efficacies of the compounds of the invention,the nature and severity of the disorder being treated and the weight ofthe mammal. However, a unit dose for a 70kg adult will normally contain0.05 to 1000 mg for example 0.1 to 500 mg, of the compound of theinvention. Unit doses may be administered once or more than once a day,for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day,that is in the range of approximately 0.0001 to 50 mg/kg/day, moreusually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated at any of theaforementioned dosage ranges.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as an activetherapeutic substance, in particular for use in the treatment of emesis,migraine, cluster headache, trigeminal neuralgia, visceral pain and/oranxiety.

The following Examples illustrate the preparation of compounds offormula (I); the following descriptions illustrate the preparation ofintermediates.

DESCRIPTION 1(endo)-2-Amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-benzamide(D1) ##STR16## A solution of 5-chloroisatoic anhydride (2.82 g) and(endo)-8 -methyl-8-azabicyclo[3.2.1]octane-3-amine (2 g) in drydimethylformamide (50 ml) was heated at 50° C. for 1 h. The reactionmixture was cooled and the solvent evaporated under reduced pressure.The residue was partitioned between chloroform and water. The organicphase was separated, dried (Na₂ SO₄) and the solvent was then evaporatedunder reduced pressure. The product was crystallised from ethyl acetateto give the title compound (D1) (1.2 g, 30%) m.p. 151°-2° C. ¹ H-NMR(CDCl₃) 270 MHz.

    ______________________________________                                        δ          7.20-7.10                                                                              (m, 2H)                                                              6.60     (d, 1H)                                                              6.40-6.20                                                                              (m, 1H)                                                              5.45     (bs, 2H)                                                             4.20     (q, 1H)                                                              3.25-3.10                                                                              (m, 2H)                                                              2.30     (s, 3H)                                                              2.35-2.05                                                                              (m, 4H)                                                              1.95-1.60                                                                              (m, 4H)                                             ______________________________________                                    

DESCRIPTION 2 5-Chloro-4-nitroanthranilic acid (D2) (Span. 371,070; C.A.P14141c[1972]) ##STR17## 2-Acetamido-5-chloro-4-nitrobenzoic acid (16 g,0.062mol) was hydrolysed in 10% sodium hydroxide solution (60 ml) andwater (40 ml) at 90° C. for two hours. The dark brown solution wascooled and acidified with 5N hydrochloric acid. The resulting brownprecipitate was collected and dried in vacuo over P₂ O₅ to give thetitle compound (12.3 g, 92%). DESCRIPTION 3(endo)-N-(8-Methyl-8-azabicyclo[3.2.1.oct-3-yl)-2-amino-5-chloro-4-nitrobenzamide(D3) ##STR18## 5-Chloro-4-nitroanthranilic acid (5.0 g, 0.023 mol) wasdissolved in dry THF (150 ml). 12.5% Phosgene in toluene solution (50ml) was added dropwise over a 30 minute period. Once addition wascomplete the mixture was heated to about 50° C. The reaction was kept atthis temperature for four hours and then cooled. The solution wasevaporated to dryness and azeotroped twice with toluene (100 ml). Theresulting residue was dissolved in dry DMF (100 ml) and the tropaneamine (3.3 g, 0.023 mol) was added. The mixture was heated to 100° C.for two hours and then stirred at room temperature for 48 hours. The DMFwas removed in vacuo and 10% potassium carbonate solution was added. Theproduct was extracted into chloroform (2×200 ml) and dried over sodiumsulphate. Evaporation to dryness gave the crude product which waspurified by column chromatography on alumina, eluting with chloroform.This gave the title compound (1.2 g, 15%). DESCRIPTION 4(endo)-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-amino-5-chloro-4-nitrobenzamide (D4) ##STR19##5-Chloro-4-nitroanthranilic acid (2.0 g, 0.0092 mol) was refluxed intoluene (65 ml) with thionyl chloride (20 ml) for four hours. Thesolution was cooled, evaporated to dryness and azeotroped once withtoluene (50 ml). The residue was dissolved in methylene chloride (100ml) and the granatane amine (1.46 g, 0.0095 mol) was added. The mixturewas stirred at room temperature for 20 hours, washed with sodiumbicarbonate solution and dried over sodium sulphate. The residue afterevaporation was purified by column chromatography on alumina (100 g),eluting with chloroform, to give the title compound (1.37 g, 40%).EXAMPLE 1(endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine(E1) ##STR20## A solution of sodium nitrite (0.3 g) in water (3 ml) wasadded dropwise to a solution of(endo)-2-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-benzamide(D1) (1.12 g) in conc. hydrochloric acid (3 ml) at 0° C. The reactionmixture was stirred at 0° C. for 11/2 h and then basified with potassiumcarbonate solution. The product was extracted into dichlomethane (2×100ml). The organic phase was dried Na₂ SO₄) and the solvent evaporatedunder reduced pressure to give, after crystallisation from ethylacetate/petrol, the title compound (E1) (1.2 g, 100%) m.p. 114°-5° C. ¹H-NMR (CDCl₃) 270 MHz.

    ______________________________________                                        δ          8.30     (d, 1H)                                                              8.05     (d, 1H)                                                              7.85     (dd, 1H)                                                             5.45-5.30                                                                              (m, 1H)                                                              3.35-3.20                                                                              (m, 2H)                                                              2.70-2.50                                                                              (m, 2H)                                                              2.30     (s, 3H)                                                              2.20-1.90                                                                              (m, 4H)                                                              1.85-1.70                                                                              (m, 2H)                                             ______________________________________                                    

EXAMPLE 2(endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-3,4-dihydro-4-oxo-1,2,3-benzotriazine(E2) ##STR21## following the procedures described in Description 1 andExample 1, isatoic anhydride was converted to the title compound E2(overall yield 30%) m.p. 75°-6° C. ¹ H-NMR (CDCl₃) 270 MHz.

    ______________________________________                                        δ          8.33     (dm, 1H)                                                             8.14     (dm, 1H)                                                             7.92     (tm, 1H)                                                             7.78     (tm, 1H)                                                             5.36     (tt, 1H)                                                             3.34-3.24                                                                              (m, 2H)                                                              2.70-2.55                                                                              (m, 2H)                                                              2.30     (s, 3H)                                                              2.20-1.75                                                                              (m, 6H)                                             ______________________________________                                    

EXAMPLE 3

(endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-7-nitro-3,4-dihydro-4-oxo-benzotriazine(E3) ##STR22## (endo)-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-amino-5chloro-4-nitrobenzamide (0.62 g, 0.0018 mol) was dissolved in 5Nsulphuric acid (4 ml) and water (10 ml) cooled to 0° C. Sodium nitrite(0.15 g, 0.0022 mol) was added and the mixture was stirred at 0° C. for1 hour. The mixture was basified with potassium carbonate and theproduct extracted into chloroform. The solution was dried over sodiumsulphate and evaporated to dryness. Recrystallisation fromethylacetate/petrol yielded the title compound (0.38 g, 60%).

m.p. 193°-9° C.

¹ H NMR (CDCl₃) 270 MHz.

    ______________________________________                                        δ          8.51     (s, 1H)                                                              8.50     (s, 1H)                                                              5.30-5.42                                                                              (m, 1H)                                                              3.25-3.35                                                                              (brs, 2H)                                                            2.56-2.70                                                                              (m, 2H)                                                              2.30     (s, 3H)                                                              2.10-2.20                                                                              (m, 2H)                                                              1.90-2.01                                                                              (m, 2H)                                                              1.65-1.78                                                                              (m, 2H)                                             ______________________________________                                    

EXAMPLE 4(endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxo-benzotriazine(E4) ##STR23## The nitro compound E3 (0.5 g, 0.014 mol) was hydrogenatedat atmospheric pressure and at 20° C. in ethanol (100 ml) over raneynickel (acid washed). After 1 hour the catalyst was filtered off and thefiltrate evaporated to dryness. The residue was extracted into methylenechloride, dried over sodium sulphate and evaporated to dryness. Theresidue was purified by column chromatography on alumina, eluting withchloroform. Recrystallisation from ethyl acetate/petrol gave the titlecompound (0.1 g, 22%)

m.p. 200°-1° C.

¹ H NMR (CDCl₃) 270 MHz.

    ______________________________________                                        δ          8.32     (s, 1H)                                                              7.40     (s, 1H)                                                              5.36-5.48                                                                              (m, 1H)                                                              4.95     (brs, 2H)                                                            3.33-3.43                                                                              (brs, 2H)                                                            2.63-2.79                                                                              (m, 2H)                                                              2.31     (s, 3H)                                                              2.17-2.25                                                                              (m, 2H)                                                              2.04-2.12                                                                              (m, 2H)                                                              1.85-1.95                                                                              (m, 2H)                                             ______________________________________                                    

EXAMPLE 5(endo)-3-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-7-nitro-3,4-dihydro-4-oxobenzotriazine(E5) ##STR24## Following the general procedure outlined in example 1,(endo)-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-amino-5-chloro-4-nitrobenzamidewas converted to the benzotriazole E5 (0.75 g, 55%). EXAMPLE 6(endo)-3-(9 Methyl)-9-azabicyclo[3.3.1]non-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxobenzotriazine (E6) ##STR25##(endo)-3-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-7-nitro-3,4-dihydro-4-oxobenzotriazine (0.75 g) was hydrogenatedas in example 4 to yield the title compound (0.36 g, 53%).

m.p. 224°-6° C.

¹ H NMR (DMSO-d⁶).

    ______________________________________                                        δ          8.11     (s, 1H)                                                              7.37     (s, 1H)                                                              5.95     (brs, 2H)                                                            5.54-5.70                                                                              (m, 1H)                                                              3.20-3.30                                                                              (brd, 2H)                                                            2.60     (s, 3H)                                                              2.31-2.47                                                                              (m, 2H)                                                              1.99-2.28                                                                              (m, 5H)                                                              1.52-1.66                                                                              (m, 1H)                                                              1.11-1.22                                                                              (m, 2H)                                             ______________________________________                                    

Following the procedures outlined in, where appropriate, Examples 1, 3and 4, the following compounds were prepared.

EXAMPLE 7 (5β)-3-(2-Methyl-2-azabicyclo[2.2.2]oct-5-yl)-6-chloro-3,4-dihydro-4-oxobenzotriazine (E7) ##STR26##

m.p. 94-98° C.

    ______________________________________                                        .sup.1 H-Nmr (CDCl.sub.3) δ:                                            ______________________________________                                                  8.30   (d, 1H)                                                                8.10   (d, 1H)                                                                7.88   (dd, 1H)                                                               5.26-5.17                                                                            (m, 1H)                                                                2.99-2.82                                                                            (m, 3H)                                                                2.79-2.72                                                                            (m, 1H)                                                                2.46   (s, 3H)                                                                2.19-1.75                                                                            (m, 5H)                                                                1.72-1.59                                                                            (m, (1H)                                                     ______________________________________                                    

EXAMPLE 8 (5β)-3-(2-Methyl-2-azabicyclo[2.2.2]oct-5-yl)-7-amino-6-chloro-3,4-dihydro-4-oxobenzotriazine (E8) ##STR27##

m.p. 290-5° C.

    ______________________________________                                        .sup.1 H-Nmr (d.sup.6 -DMSO) δ:                                         ______________________________________                                        8.03         (s, 1H)                                                          7.39         (s, 1H)                                                          6.38         (brs, 2H)                                                        5.30-5.18    (m, 1H)                                                          3.55         (brs, 1H)                                                        3.00-2.75    (m, 5H including 2.89, s, 3H)                                    2.55-2.28    (m, 3H)                                                          2.05-1.80    (m, 4H)                                                          ______________________________________                                    

EXAMPLE 9 3-(1-Azabicyclo[2.2.2]oct-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxobenzotriazine (E9) ##STR28##

m.p. 243-6° C.

    ______________________________________                                        .sup.1 H-Nmr (d.sup.6 -DMSO) δ:                                         ______________________________________                                                  7.99   (s, 1H)                                                                7.31   (s, 1H)                                                                6.59   (brs, 2H)                                                              5.12-5.02                                                                            (m, 1H)                                                                3.47   (dd, 1H)                                                               3.26   (t, 1H)                                                                3.12-2.95                                                                            (m, 1H)                                                                2.89-2.70                                                                            (m, 3H)                                                                2.12-2.03                                                                            (m, 1H)                                                                1.85-1.60                                                                            (m, 3H)                                                                1.45-1.30                                                                            (m, 1H)                                                      ______________________________________                                    

EXAMPLE 10 (endo)-3-(8-Methyl-8-azabicyclo[3.2.1I]oct-2-yl)-7-amino-6-bromo-3,4-dihydro-4-oxobenzotriazine (E10) ##STR29##

m.s. M⁺ 363,

    ______________________________________                                        .sup.1 H-Nmr (CDCl.sub.3) δ:                                            ______________________________________                                                  8.40   (s, 1H)                                                                7.26   (s, 1H)                                                                5.32   (dt, 1H)                                                               4.90   (brs, 2H)                                                              3.28   (brs, 2H)                                                              2.70-2.50                                                                            (m, 2H)                                                                2.30   (s, 3H)                                                                2.15-2.02                                                                            (m, 2H)                                                                1.96   (dd, 2H)                                                               1.85-1.70                                                                            (m, 2H)                                                      ______________________________________                                    

EXAMPLE 11 (endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6chlor-7-nitro-3,4-dihydro-4-oxoquinazoline (E11) ##STR30## A mixture ofintermediate D3 (0.44 g), conc. H2SO₄ (2 drops) and triethylorthoformate(10m) was heated under reflux for 30h. The reaction mixture wasevaporated to dryness and the residue partitioned between CHCl₃ (50ml)and NaHC₀₃ solution (20 ml). The separated organic layer was dried (K₂CO₃), evaporated to dryness and the residue purified by columnchromatography on alumina, eluting with CHCl₃, to give the titlecompound (0.22 g).

m.s. M⁺ 348.350.

    ______________________________________                                        .sup.1 H-Nmr (CDCl.sub.3) δ:                                            ______________________________________                                        8.43         (s, 1H)                                                          8.11         (s, 1H)                                                          8.07         (s, 1H)                                                          4.89         (tt, 1H)                                                         3.40-3.30    (m, 2H)                                                          2.63-2.48    (m, 2H)                                                          2.30-2.15    (m, 5H including 2.24, s, 3H)                                    1.82-1.60    (4H)                                                             ______________________________________                                    

EXAMPLE 12 (endo)-3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxoquinazoline (E12) ##STR31## Followingthe procedures outlined in Example 4, the nitro compound (E11) (0.21 g)was converted to the title compound (0.15 g). m.s. 318.320.

    ______________________________________                                        .sup.1 H-Nmr (CDCl.sub.3)δ:                                             ______________________________________                                        8.16         (s, 1H)                                                          7.92         (s, 1H)                                                          6.89         (s, 1H)                                                          4.77         (tt, 1H)                                                         4.60         (brs, 2H)                                                        3.35-3.25    (m, 2H)                                                          2.60-2.42    (m, 2H)                                                          2.28-2.12    (m, 5H including 2.22, s, 3H)                                    1.85-1.70    (m, 4H)                                                          ______________________________________                                    

PHARMACOLOGY Antagonism of the von Bezold-Jarisch reflex

The compounds were evaluated for antagonism of the von Bezold-Jarischreflex evoked by 5-HT in the anaesthetised rat according to thefollowing method:

Male rats, 250-350 g, were anaesthetised with urethane (1.25 g/kgintraperitoneally) and blood pressure and heart rate recorded asdescribed by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245(1980). A submaximal dose of 5-HT (usually 6 μg/kg) was given repeatedlyby the intravenous route and changes in heart rate quantified. Compoundswere given intravenously and the concentration required to reduce the5HT-evoked response to 50% of the control response (ED₅₀) was thendetermined.

The results were as follows:

    ______________________________________                                        Compound      ED.sub.50 μg/kg i.v.                                         ______________________________________                                        E1            12                                                              E3            13                                                              E4            0.17                                                            E8            6                                                               ______________________________________                                    

I claim:
 1. A compound of formula (I), or a pharmaceutically acceptablesalt thereof: ##STR32## wherein X is N;R₁ and R₂ are the same ordifferent and are hydrogen, halogen, CF₃, C₁₋₆ alkyl, C₁₋₇ acyl, C₁₋₇acylamino, or amino, aminocarbonyl or aminosulphonyl, optionallysubstituted by one or two C₁₋₆ alkyl or C₃₋₈ cycloalkyl groups, or byC₄₋₅ polymethylene or by phenyl, C₁₋₆ alkylsulphonyl, C₁₋₆alkylsuphinyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy or nitro; or R₁ andR₂ taken together are methylenedioxy or ethylenedioxy; Z is a group offormula (a), (b) or (c) ##STR33## wherein n is 2 or 3; p is 1 or 2; q is1 to 3; r is 1 to 3; and R₃ or R₄ is C₁₋₄ alkyl.
 2. A compound accordingto claim 1 of formula (II): ##STR34## wherein R₁, R₂, R₃, X and n are asdefined in claim
 1. 3. A compound according to claim 2 wherein n is 2.4. A compound according to claim 2 wherein R₃ or R₄ is methyl.
 5. Acompound according to claim 1 of formula (III): ##STR35## wherein q¹ is1 or 2 and R₁ R₂ and X are as defined in claim
 1. 6. A compoundaccording to claim 5 wherein q is
 2. 7. A compound according to claim 1wherein R₁ is hydrogen, 7-chloro or 7-bromo and R₂ is hydrogen; or R₁ is7-amino and R₂ is 6-chloro or 6-bromo.
 8. A compound selected from thegroup consisting of(endo)-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-7-nitro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-7-amino-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-7-nitro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(5β)-3-(2-methyl-2-azabicyclo[2.2.2]oct-5-yl)-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(5β)-3-(2-methyl-2-azabicyclo[2.2.2]oct-5-yl)-7-amino-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,3-(1-azabicyclo[2.2.2]oct-3-yl)-7-amino-6-chloro-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(endo)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7-amino-6-bromo-3,4-dihydro-4-oxo-1,2,3-benzotriazine,or a pharmaceutically acceptable salt of any of the foregoing.
 9. Apharmaceutical composition comprising a 5-HT₃ antagonist effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 10. A method of treatment of emesis, migraine,cluster headache, trigeminal neuralgia, visceral pain or anxiety inmammals, which comprises the administration of an effective amount of acompound according to claim 1.